Hemorrhagic Shock (HS) combined with tissue trauma act together to initiate a cascade of signaling events that culminate in inflammation and end-organ damage and dysfunction. The molecular basis for the activation of inflammatory signaling cascades following injury are poorly understood. It has been the premise of our research that understanding how injury induced inflammation is initiated, amplified and then propagated will lead to resuscitation strategies that will control both the early hyperinflammation and the delayed immunocompromised state that develops in trauma patients. It is our hypothesis that signaling events begin almost immediately after injury, and that multiple overlapping pathways are activated that act in concert to amplify and propagate the systemic inflammatory response. We have accumulated data demonstrating that MAP kinases are activated early following the induction of HS in response to hypoxia and circulating hormones. This is followed by the upregulation of the transcriptional factor early growth response gene-1, (Egr-1), and the expression of the inducible NO synthase (iNOS) also during HS and prior to resuscitation. Furthermore, we have evidence showing that both Egr-1 and iNOS participate in the post-resuscitation inflammatory response. We now propose two aims to determine the regulatory relationships between reactive oxygen species, MAP kinases (JNK and ERK), Egr-1, and iNOS during shock and the functional roles of these pathways in controlling post-resuscitation inflammation. The aims are as follows: AIM I: To determine the pathways to MAPK activation and Egr-1 and iNOS upregulation following trauma and shock. Under this aim we will explore the role of reactive oxygen species to the upregulafion of MAP kinases, Egr-1 and iNOS. In addition, we will determine whether there is a dependent sequence in the activation of the three pathways. AIM II: To determine the mechanistic relationships between MAP kinase activation, and Egr-1 and iNOS upregulation to the post-resuscitation intlammation and organ damage. Experiments under Aim II will take advantage of the regulatory information gained in Aim I to determine the role of MAP kinases, Egr-1 and iNOS in controlling the post-resuscitation inflammatory response. With the completion of our two aims we will have established the molecular relationship between these pathways and their individual as well as synergistic roles controlling post-resuscitation inflammation. Each pathway represents a potential target for the further development of therapeutic strategies designed to attenuate the magnitude of the systemic inflammatory response following injury.